Targeted disruption of the voltage-dependent calcium channel α2/δ-1-subunit

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Abstract
Cardiac L-type voltage-dependent Ca2+channels are heteromultimeric polypeptide complexes of α1-, α2/δ-, and β-subunits. The α2/δ-1-subunit possesses a stereoselective, high-affinity binding site for gabapentin, widely used to treat epilepsy and postherpetic neuralgic pain as well as sleep disorders. Mutations in α2/δ-subunits of voltage-dependent Ca2+channels have been associated with different diseases, including epilepsy. Multiple heterologous coexpression systems have been used to study the effects of the deletion of the α2/δ-1-subunit, but attempts at a conventional knockout animal model have been ineffective. We report the development of a viable conventional knockout mouse using a construct targeting exon 2 of α2/δ-1. While the deletion of the subunit is not lethal, these animals lack high-affinity gabapentin binding sites and demonstrate a significantly decreased basal myocardial contractility and relaxation and a decreased L-type Ca2+current peak current amplitude. This is a novel model for studying the function of the α2/δ-1-subunit and will be of importance in the development of new pharmacological therapies.

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